Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody-Positive Primary Membranous Nephropathy.

Introduction: Primary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN. Methods: Patients with newly diagnosed or relapsed PMN (cohort 1 [C1]; n = 18) or PMN refractory to immunosuppressive therapy (IST) (cohort 2 [C2]; n = 13) received 9 infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary end point was the incidence and severity of treatment-emergent adverse events (TEAEs). Results: A total of 31 patients were enrolled and received felzartamab. Twenty-seven patients (87.1%) had TEAEs, including infusion-related reactions (IRRs) (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five patients (16.1%) had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20 of 26 efficacy-evaluable patients (76.9%) (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (urine protein-to-creatinine ratio [UPCR] reduction ≥50%, UPCR <3.0 g/g, and stable estimated glomerular filtration rate [eGFR]) was achieved by 9 of 26 patients (34.6%) (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20 of 26 patients (76.9%) (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]). Conclusion: In this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.

Association between dietary magnesium intake and incident chronic kidney disease: a prospective observational cohort study.

BACKGROUND: Although serum magnesium deficiency is linked to higher cardiovascular disease risk, its association with chronic kidney disease (CKD) remains unclear. OBJECTIVES: This study aimed to evaluate the relationship between dietary magnesium intake and CKD development in adults with clinically normal kidney function. METHODS: The prospective observational cohort study evaluated 188,510 participants (median age, 57.0 y; female, 54.1%) from the UK Biobank. Dietary magnesium intake was assessed through a 24-h dietary recall questionnaire compromising a list of 206 foods and 32 beverages and categorized into quintiles. The primary outcome was incident CKD diagnosed through International Classification of Diseases-10 and Office of Population Censuses and Surveys 4 codes. Incident CKD, defined as estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, was also assessed in a subcohort with creatinine follow-up data. RESULTS: The median magnesium intake amount per person was 323.2 mg/d [interquartile range (IQR): 269.4-382.7 mg/d]. During 1,826,038.1 person-years of follow-up (median: 9.6 y; IQR: 9.3-10.3 y), CKD developed in 5,878 participants. The incidence of CKD was progressively higher in participants with lower magnesium intake (2.8%, 2.8%, 3.0%, 3.2%, and 3.7% in Q5-Q1, respectively). Cox regression analysis revealed that the hazard ratios (HRs) for incident CKD increased in a stepwise manner toward lower magnesium intake quintiles {adjusted HR (95% confidence interval [CI])-Q4: 0.97 (0.89, 1.06); Q3: 1.05 (0.96, 1.14); Q2: 1.12 (1.03, 1.21); Q1: 1.30 (1.20, 1.41)} relative to Q5 (P-linearity < 0.001). Similar results were observed with eGFR-defined CKD outcome [adjusted HR (95% CI)-Q4: 1.09 (0.92, 1.28); Q3: 1.15 (0.98, 1.35); Q2: 1.21 (1.03, 1.42); Q1: 1.41 (1.20, 1.65) relative to Q5; P-linearity < 0.001]. CONCLUSIONS: Lower dietary magnesium intake was associated with higher risk of incident CKD in adults with clinically normal kidney function. Further controlled studies are required to establish the potential benefit of adequate magnesium intake.

Multifaceted association of overweight and metabolically unhealthy with the risk of Barrett's esophagus in the UK Biobank cohort.

The association of overweight/obesity and metabolically unhealthy (MU) with the risk of developing Barrett's esophagus (BE) remains uncertain. We evaluated whether MU and overweight/obesity are associated with increased BE incidence and whether they have a synergistic impact on BE development. We analyzed the body mass index (BMI) and metabolic indicators at baseline of 402,510 individuals from the UK Biobank with no history of BE. Overweight/obesity and MU were defined as BMI ≥ 25.0 kg/m2 and presence of ≥ 1 MU indicators, respectively. Accordingly, the participants were categorized into four groups: (1) metabolically healthy non-overweight/obesity (MHNO), (2) metabolically unhealthy non-overweight/obesity (MUNO), (3) metabolically healthy overweight/obesity (MHO), and (4) metabolically unhealthy overweight/obesity (MUO). During a median follow-up of 13.5 years, 6195 (1.5%) individuals were newly diagnosed with BE. Among them, 39,281 (9.8%), 92,000 (22.9%), 25,297 (6.3%), and 245,932 (61.1%) individuals were classified as MHNO, MUNO, MHO, and MUO, respectively. In Cox regression analyses, both MU and overweight/obesity were independently associated with BE incidence. Moreover, BE incidence was significantly higher in the MUNO, MHO, and MUO groups, compared to the MHNO group. MU and overweight/obesity are independent risk factors for BE and have a synergistic effect on BE development.

Hospitalization among adults with chronic kidney disease: results from the KoreaN cohort study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD) study.

Background: Chronic kidney disease (CKD) patients are hospitalized for various conditions. Hospitalization increases the readmission rate and mortality rate, seriously deteriorating patients' quality of life. Consequently, it is crucial to analyze the reasons for hospitalization in CKD patients from a broader perspective according to CKD grade. Methods: This is a prospective cohort study of CKD patients entitled the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). A total of 2,238 patients were examined, and the reasons for hospitalization were classified into 16 disease categories. The incidence rate ratio (IRR) according to CKD stage was compared using negative bimodal regression analysis. Results: The all-cause hospitalization incidence was 184.96 per 1,000 person-years. The most common reason for hospitalization was circulatory system disease, followed by infection and digestive system disease. Among hospitalizations for acute kidney injury, endocrine-nutrition-metabolic-related illness, blood-related disease, and diseases of the nervous system and sensory organs, IRR increased as CKD grade advanced. The incidence of ophthalmologic surgery during hospitalization increased according to the CKD stage. The IRR of KNOW-CKD patients was 6.19 (95% confidence interval, 5.92-6.48; p < 0.001) compared with the general population. Conclusion: This in-depth analysis of hospitalizations among CKD patients confirmed that CKD patients were hospitalized for various reasons, such as metabolic, ophthalmic, and hematologic diseases. Early detection and intervention regarding causative diseases of CKD are important to reduce the hospitalization burden and improve patients' quality of life.

The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease.

AIMS/HYPOTHESIS: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD. METHODS: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions. RESULTS: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes. CONCLUSIONS/INTERPRETATION: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.

Volume control strategy and patient survival in sepsis-associated acute kidney injury receiving continuous renal replacement therapy: a randomized controlled trial with secondary analysis.

Optimal strategy for volume control and the clinical implication of achieved volume control are unknown in patients with sepsis-associated acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT). This randomized controlled trial aimed to compare the survival according to conventional or bioelectrical impedance analysis (BIA)-guided volume control strategy in patients with sepsis-associated AKI receiving CRRT. We also compared patient survival according to achieved volume accumulation rate ([cumulative fluid balance during 3 days × 100]/fluid overload measured by BIA at enrollment) as a post-hoc analysis. We randomly assigned patients to conventional volume control strategy (n = 39) or to BIA-guided volume control strategy (n = 34). There were no differences in 28-day mortality (HR, 1.19; 95% CI, 0.63-2.23) or 90-day mortality (HR, 0.99; 95% CI 0.57-1.75) between conventional and BIA-guided volume control group. In the secondary analysis, achieved volume accumulation rate was significantly associated with patient survival. Compared with the achieved volume accumulation rate of ≤ - 50%, the HRs (95% CIs) for the risk of 90-day mortality were 1.21 (0.29-5.01), 0.55 (0.12-2.48), and 7.18 (1.58-32.51) in that of - 50-0%, 1-50%, and > 50%, respectively. Hence, BIA-guided volume control in patients with sepsis-associated AKI receiving CRRT did not improve patient outcomes. In the secondary analysis, achieved volume accumulation rate was associated with patient survival.

Adequacy of Dialysis and Incidence of Atrial Fibrillation in Patients Undergoing Hemodialysis.

BACKGROUND: Atrial fibrillation (AF) can lead to stroke, heart failure, and mortality and has a greater prevalence in dialysis patients than in the general population. Several studies have suggested that uremic toxins may contribute to the development of AF. However, the association between dialysis adequacy and incident AF has not been well established. METHODS: In this retrospective nationwide cohort study, we analyzed data from the Korean National Periodic Hemodialysis Quality Assessment from 2013 to 2015 of patients who received outpatient maintenance hemodialysis 3× a week. The main exposure was single pooled Kt/V (spKt/V), which is the dialysis adequacy index, and the primary outcome was the development of AF. For the primary analysis, patients were categorized into quartiles according to baseline spKt/V. The lowest quartile, representing the lowest adequacy, was used as the reference group. Fine-Gray subdistribution hazard models were used, treating all-cause mortality as a competing risk. RESULTS: Of 25 173 patients, the mean age was 60 (51-69) years, and 14 772 (58.7%) were men. During a median follow-up of 5.7 years, incident AF occurred in a total of 3883 (15.4%) patients. Participants with a higher spKt/V tended to have lower AF incidence. In survival analysis, a graded association was observed between the risk of incident AF and spKt/V quartiles: subdistribution hazard ratios and 95% CIs for the second, third, and the highest quartile compared with the lowest quartile were 0.90 (95% CI, 0.82-0.98), 0.84 (95% CI, 0.77-0.93), and 0.79 (95% CI, 0.72-0.88), respectively. CONCLUSIONS: This nationwide cohort study showed that a higher spKt/V is associated with a reduced risk of incident AF. These findings suggests that reducing uremic toxin burden through enhanced dialysis clearance may be associated with a lower risk of AF development in patients undergoing maintenance hemodialysis.

Triglyceride-glucose index is an independent predictor of coronary artery calcification progression in patients with chronic kidney disease.

BACKGROUND: Coronary artery calcification (CAC) is highly prevalent in patients with chronic kidney disease (CKD) and is associated with major adverse cardiovascular events and metabolic disturbances. The triglyceride-glucose index (TyGI), a novel surrogate marker of metabolic syndrome and insulin resistance, is associated with CAC in the general population and in patients with diabetes. This study investigated the association between the TyGI and CAC progression in patients with CKD, which is unknown. METHODS: A total of 1,154 patients with CKD (grades 1-5; age, 52.8 ± 11.9 years; male, 688 [59.6%]) were enrolled from the KNOWCKD (KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease). The TyGI was calculated as follows: ln (fasting triglycerides × fasting glucose/2). Patients were classified into tertiles (low, intermediate, high) based on the TyGI. The primary outcome was annualized percentage change in CAC score [(percent change in CAC score + 1)12/follow-up months - 1] of ≥15%, defined as CAC progression. RESULTS: During the 4-year follow-up, the percentage of patients with CAC progression increased across TyGI groups (28.6%, 37.5%, and 46.2% in low, intermediate, and high groups, respectively; p < 0.001). A high TyGI was associated with an increased risk of CAC progression (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.14-3.88; p = 0.02) compared to the low group. Moreover, a 1-point increase in the TyGI was related to increased risk of CAC progression (OR, 1.55; 95% CI, 1.06-1.76; p = 0.02) after adjustment. CONCLUSION: A high TyGI may be a useful predictor of CAC progression in CKD.

Lactobacillus acidophilus KBL409 protects against kidney injury via improving mitochondrial function with chronic kidney disease.

PURPOSE: Recent advances have led to greater recognition of the role of mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD). There has been evidence that CKD is also associated with dysbiosis. Here, we aimed to evaluate whether probiotic supplements can have protective effects against kidney injury via improving mitochondrial function. METHODS: An animal model of CKD was induced by feeding C57BL/6 mice a diet containing 0.2% adenine. KBL409, a strain of Lactobacillus acidophilus, was administered via oral gavage at a dose of 1 × 109 CFU daily. To clarify the underlying mechanisms by which probiotics exert protective effects on mitochondria in CKD, primary mouse tubular epithelial cells stimulated with TGF-ß and p-cresyl sulfate were administered with butyrate. RESULTS: In CKD mice, PGC-1α and AMPK, key mitochondrial energy metabolism regulators, were down-regulated. In addition, mitochondrial dynamics shifted toward fission, the number of fragmented cristae increased, and mitochondrial mass decreased. These alterations were restored by KBL409 administration. KBL409 supplementation also improved defects in fatty acid oxidation and glycolysis and restored the suppressed enzyme levels involved in TCA cycle. Accordingly, there was a concomitant improvement in mitochondrial respiration and ATP production assessed by mitochondrial function assay. These favorable effects of KBL409 on mitochondria ultimately decreased kidney fibrosis in CKD mice. In vitro analyses with butyrate recapitulated the findings of animal study. CONCLUSIONS: This study demonstrates that administration of the probiotic Lactobacillus acidophilus KBL409 protects against kidney injury via improving mitochondrial function.

Association between progression of coronary artery calcification and development of kidney failure with replacement therapy: Findings from KNOW-CKD study.

BACKGROUND AND AIMS: High coronary artery calcification (CAC) burden is a significant risk factor for adverse cardiovascular and kidney outcomes. However, it is unknown whether changes in the coronary atherosclerotic burden can accompany changes in kidney disease progression. Here, we evaluated the relationship between CAC progression and the risk of kidney failure with replacement therapy (KFRT). METHODS: We analyzed 1173 participants with chronic kidney disease (CKD) G1 to G5 without kidney replacement therapy from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Participants were categorized into three groups according to the change in the CAC score between enrollment and year 4 (non-progressors, ≤0 AU; moderate progressors, 1-199 AU; and severe progressors, ≥200 AU). The primary outcome was the development of KFRT. RESULTS: During a follow-up period of 4690 person-years (median, 4.2 years), the primary outcome occurred in 230 (19.6 %) participants. The incidence of KFRT was 37.6, 54.3, and 80.9 per 1000 person-years in the non-, moderate, and severe progressors, respectively. In the multivariable cause-specific hazard model, the hazard ratios (HRs) for the moderate and severe progressors were 1.71 (95 % confidence interval [CI], 1.02-2.87) and 2.55 (95 % CI, 1.07-6.06), respectively, compared with non-progressors. A different definition of CAC progression with a threshold of 100 AU yielded similar results in a sensitivity analysis. CONCLUSIONS: CAC progression is associated with an increased risk of KFRT in patients with CKD. Our findings suggest that coronary atherosclerosis changes increase the risk of CKD progression.

Glomerulonephritis following COVID-19 infection or vaccination: a multicenter study in South Korea.

BACKGROUND: Despite the widespread impact of the severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019, COVID-19) and vaccination in South Korea, our understanding of kidney diseases following these events remains limited. We aimed to address this gap by investigating the characteristics of glomerular diseases following the COVID-19 infection and vaccination in South Korea. METHODS: Data from multiple centers were used to identify de novo glomerulonephritis (GN) cases with suspected onset following COVID-19 infection or vaccination. Retrospective surveys were used to determine the COVID-19-related histories of patients who were initially not implicated. Bayesian structural time series and autoregressive integrated moving average models were used to determine causality. RESULTS: Glomerular diseases occurred shortly after the infection or vaccination. The most prevalent postinfection GN was podocytopathy (42.9%), comprising primary focal segmental glomerulosclerosis and minimal change disease, whereas postvaccination GN mainly included immunoglobulin A nephropathy (IgAN; 57.9%) and Henoch-Schönlein purpura nephritis (HSP; 15.8%). No patient progressed to end-stage kidney disease. Among the patients who were initially not implicated, nine patients with IgAN/HSP were recently vaccinated against COVID-19. The proportion of glomerular diseases changed during the pandemic in South Korea, with an increase in acute interstitial nephritis and a decrease in pauci-immune crescentic GN. CONCLUSION: This study showed the characteristics of GNs following COVID-19 infection or vaccination in South Korea. Understanding these associations is crucial for developing effective patient management and vaccination strategies. Further investigation is required to fully comprehend COVID-19's impact on GN.

Association of ketone bodies with incident CKD and death: A UK Biobank study.

AIMS: Although cellular and animal models have suggested a protective effect of ketone bodies (KBs), clinical data are still lacking to support these findings. This study aimed to investigate the association of KB levels with incident chronic kidney disease (CKD) and death. METHODS: This was a prospective cohort study of 87,899 UK Biobank participants without baseline CKD who had plasma levels of ß-hydroxybutyrate, acetoacetate, and acetone levels measured at the time of enrollment. The main predictor was plasma total KB, which was the sum of the aforementioned three KBs. The primary outcome was a composite of incident CKD, or all-cause mortality. Secondary outcomes included the individual components of the primary outcome. RESULTS: During a median follow-up of 11.9 years, a total of 8,145 primary outcome events occurred (incidence rate 8.0/1,000 person-years). In the multivariable Cox model, a 1-standard deviation increase in log total KB was associated with a 7 % [adjusted hazard ratio (aHR), 1.07; 95 % confidence interval (CI), 1.05-1.10] higher risk of the primary outcome. When stratified into quartiles, the aHR (95 % CI) for Q4 versus Q1 was 1.18 (1.11-1.27). This association was consistent for incident CKD (aHR, 1.04; 95 % CI, 1.01-1.07), and all-cause mortality (aHR, 1.10; 95 % CI, 1.07-1.13). Compared with Q1, Q4 was associated with a 12 % (aHR 1.12; 95 % CI 1.02-1.24) and 26 % (aHR 1.26; 95 % CI 1.15-1.37) higher risk of incident CKD and all-cause mortality, respectively. CONCLUSIONS: Higher KB levels were independently associated with higher risk of incident CKD and death.

Higher potassium intake is associated with a lower risk of chronic kidney disease: population-based prospective study.

BACKGROUND: High-potassium intake is associated with a lower risk of cardiovascular disease. However, the association between potassium intake and the development of chronic kidney disease (CKD) remains unclear. OBJECTIVE: The objective of this study was to investigate whether potassium intake is associated with outcomes of incident CKD. METHODS: This is a population-based prospective observational cohort study from the UK Biobank cohort between 2006 and 2010. We included 317,162 participants without CKD from the UK Biobank cohort. The main predictor was spot urine potassium-to-creatinine ratio (KCR). The primary outcome was incident CKD, which was defined by the International Classification of Disease 10 codes or Operating Procedure Codes Supplement 4 codes. RESULTS: At baseline, individuals with higher KCR had lower blood pressure, body mass index, and inflammation, and were less likely to have diabetes and hypertension. During a median follow-up of 11.9 y, primary outcome events occurred in 15,246 (4.8%) participants. In the cause-specific model, the adjusted hazard ratio (aHR) per 1-standard deviation increase in KCR for incident CKD was 0.90 [95% confidence interval (CI): 0.89, 0.92]. Compared with quartile 1 of KCR, the aHRs (95% CIs) for quartiles 2-4 were 0.98 (0.94, 1.02), 0.90 (0.86, 0.95), and 0.80 (0.76, 0.84), respectively. In sensitivity analysis with different definitions of CKD, the results were similar. In addition, further analysis with dietary potassium intake also showed a negatively graded association with the primary outcome. CONCLUSIONS: Higher urinary potassium excretion and intake were associated with a lower risk of incident CKD.

Plasma Levels of Polyunsaturated Fatty Acids and Adverse Kidney Outcomes.

RATIONALE & OBJECTIVE: Many studies have reported polyunsaturated fatty acids (PUFA) as significant predictors of cardiovascular disease, but little is known about the relationship between PUFA levels and chronic kidney disease (CKD). This study explored this relationship among individuals with and without CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 73,419 participants without CKD (cohort 1) and 6,735 participants with CKD (cohort 2) in the UK Biobank Study, with PUFA levels measured between 2007 and 2010. EXPOSURE: Percentage of plasma PUFA, omega-3 fatty acid (FA), omega-6 FA, docosahexaenoic acid (DHA), and linoleic acid relative to total FA. OUTCOME: Incident CKD for cohort 1 and incident kidney failure requiring replacement therapy (KFRT) for cohort 2. ANALYTICAL APPROACH: Cox proportional hazards regression analyses, including a cause-specific competing risk model. RESULTS: In cohort 1, individuals with higher quartiles of plasma PUFA levels had healthier lifestyles and fewer comorbidities. During 841,007 person-years of follow-up (median 11.9 years), incident CKD occurred in 4.5% of participants (incidence rate, 39.1 per 10,000 person-years). For incident CKD in cohort 1, the adjusted cause-specific hazard ratios for quartiles 2, 3, and 4 were 0.83 (95% CI, 0.75-0.92), 0.85 (95% CI, 0.76-0.96), 0.71 (95% CI, 0.62-0.82), respectively, compared with quartile 1. This inverse relationship was consistently observed for all PUFA types. In cohort 2, although total PUFA levels were not associated with KFRT, higher PUFA subtype levels of DHA were associated with a lower risk of KFRT. LIMITATIONS: Observational design and limited generalizability to individuals with higher disease severity; no data on eicosapentaenoic acid. CONCLUSIONS: Among individuals without CKD, higher plasma PUFA levels and all 4 PUFA components were associated with a lower risk of incident CKD. In individuals with CKD, only the omega-3 component of PUFA, DHA, was associated with a lower risk of KFRT. PLAIN-LANGUAGE SUMMARY: Low amounts of polyunsaturated fatty acids (PUFA) in the blood are suspected of increasing the chances of heart disease, but it is not known whether the PUFA relates to kidney disease occurrence. In a large group without kidney disease in the United Kingdom, people with higher levels of PUFA in their blood tended to have a lower risk of developing kidney disease compared to those with lower PUFA levels. This relationship was consistently observed for all PUFA types. However, in the group with kidney disease, only higher levels of docosahexaenoic acid, a subtype of PUFAs, were associated with a lower risk of developing severe kidney problems that required kidney replacement therapy. These findings suggest that higher levels of PUFA, found in certain healthy fats, might protect against the development of kidney disease in the general population. As kidney function declines, only the docosahexaenoic acid, a subtype of PUFA, appears to be associated with preserved kidney function.

Metabolically Abnormal Non-Obese Phenotype Is Significantly Associated with All-Cause Mortality in Hemodialysis Patients.

The association between obesity and all-cause mortality in patients undergoing kidney failure with replacement therapy (KFRT) has shown conflicting results. This study aimed to evaluate whether metabolic abnormalities (MA) increase the risk of all-cause mortality in these patients. Between 2009 and 2015, 1141 patients undergoing KFRT were recruited from the Clinical Research Center for End-Stage Renal Disease dataset. Patients were divided into four groups according to the presence of obesity and MA. Multivariate Cox proportional hazard analysis was performed to determine the association between the phenotypes and all-cause mortality. During a mean follow-up of 4.2 years, all-cause mortality was observed in 491 (43.0%) patients. Obesity had a 24% decreased risk of all-cause mortality compared with non-obesity. In contrast, the presence of MA showed a 1.53-fold increased risk of all-cause mortality. There was a significant interaction between obesity and MA (p = 0.006). In Cox proportional hazard analyses after adjustment of confounding factors, the metabolically abnormal non-obesity (MANO) phenotype showed a 1.63-fold increased risk of all-cause mortality compared with the metabolically healthy non-obesity phenotype. In subgroup analysis, the risk of all-cause mortality was higher in the MANO phenotype; this phenotype was significantly associated with a higher all-cause mortality in patients undergoing KFRT.

Sweetened Beverage Intake and Incident Chronic Kidney Disease in the UK Biobank Study.

Importance: An increasing body of evidence indicates an association between consuming sugar or its alternatives and cardiometabolic diseases. However, the effects of the consumption of sugar-sweetened beverages, artificially sweetened beverages, and natural juices on kidney health remain unclear. Objective: To investigate the association of the intake of sugar-sweetened beverages, artificially sweetened beverages, and natural juices with the risk of chronic kidney disease (CKD), and the effect of substituting these beverage types for one another on this association. Design, Setting, and Participants: This prospective, population-based cohort study analyzed data from the UK Biobank. Participants without a history of CKD who completed at least 1 dietary questionnaire were included. The follow-up period was from the date of the last dietary questionnaire until October 31, 2022, in England; July 31, 2021, in Scotland; and February 28, 2018, in Wales. Data were analyzed from May 1 to August 1, 2023. Exposures: Consumption of sugar-sweetened beverages, artificially sweetened beverages, and natural juices. Main Outcomes and Measures: The primary outcome was incident CKD. Multivariable Cox proportional hazards models were used to estimate the associations between the 3 beverage types and incident CKD. A substitution analysis was used to evaluate the effect on the associations of substituting one beverage type for another. Results: A total of 127 830 participants (mean [SD] age, 55.2 [8.0] years; 66 180 female [51.8%]) were included in the primary analysis. During a median (IQR) follow-up of 10.5 (10.4-11.2) years, 4459 (3.5%) cases of incident CKD occurred. The consumption of more than 1 serving per day of sugar-sweetened beverages was associated with higher risk of incident CKD (adjusted hazard ratio [AHR], 1.19 [95% CI, 1.05-1.34]) compared with not consuming sugar-sweetened beverages. The AHR for participants consuming more than 0 to 1 serving per day of artificially sweetened beverages was 1.10 (95% CI, 1.01-1.20) and for consuming more than 1 serving per day was 1.26 (95% CI, 1.12-1.43) compared with consuming no artificially sweetened beverages. By contrast, there was no significant association between natural juice intake and incident CKD (eg, for >1 serving per day: HR, 0.99 [95% CI, 0.87-1.11]; P = .10). Substituting sugar-sweetened beverages with artificially sweetened beverages did not show any significant difference in the risk of CKD (HR, 1.03 [95% CI, 0.96-1.10]). Conversely, replacing 1 serving per day of sugar-sweetened beverage with natural juice (HR, 0.93 [95% CI, 0.87-0.97]) or water (HR, 0.93 [95% CI, 0.88-0.99]) or replacing 1 serving per day of artificially sweetened beverage with natural juice (HR, 0.90 [95% CI, 0.84-0.96]) or water (HR, 0.91 [95% CI, 0.86-0.96]) was associated with a reduced risk of incident CKD. Conclusions and Relevance: Findings from this cohort study suggest that lower consumption of sugar-sweetened beverages or artificially sweetened beverages may reduce the risk of developing CKD.

Difference Between Estimated GFR Based on Cystatin C Versus Creatinine and Incident Atrial Fibrillation: A Cohort Study of the UK Biobank.

RATIONALE & OBJECTIVE: The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFRdiff) has been suggested to reflect factors distinct from kidney function that are associated with cardiovascular risk. However, the association between eGFRdiff and atrial fibrillation (AF) risk has not been extensively evaluated. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Using data from the UK Biobank, this study included 363,494 participants with measured serum creatinine and cystatin C levels and without a prior diagnosis of AF or a history of related procedures. EXPOSURE: Estimated GFRdiff, calculated as cystatin C-based eGFR minus creatinine-based eGFR. Estimated GFRdiff was also categorized as negative (<-15mL/min/1.73m2), midrange (-15 to 15mL/min/1.73m2), or positive (≥15mL/min/1.73m2). OUTCOME: Incident AF. ANALYTICAL APPROACH: Subdistribution hazard models were fit, treating death that occurred before development of AF as a competing event. RESULTS: During the median follow-up period of 11.7 years, incident AF occurred in 18,994 (5.2%) participants. In the multivariable-adjusted model, participants with a negative eGFRdiff had a higher risk of incident AF (subdistribution HR [SHR], 1.25 [95% CI, 1.20-1.30]), whereas participants with a positive eGFRdiff had a lower risk of AF (SHR, 0.81 [95% CI, 0.77-0.87]) compared with those with a midrange eGFRdiff. When eGFRdiff was treated as a continuous variable in the adjusted model, every 10mL/min/1.73m2 higher eGFRdiff was associated with a 0.90-fold decrease in the risk of incident AF. LIMITATIONS: A single measurement of baseline serum creatinine and cystatin C levels. CONCLUSIONS: The difference between cystatin C- and creatinine-based eGFRs was associated with the risk of AF development. A higher eGFRdiff was associated with a lower risk of AF. These findings may have implications for the management of patients at risk of incident AF. PLAIN-LANGUAGE SUMMARY: The difference between cystatin C-based estimated glomerular filtration rate (eGFR) and creatinine-based eGFR has recently gained attention as a potential indicator of cardiovascular outcomes influenced by factors other than kidney function. This study investigated the association between the differences in 2 eGFRs (cystatin C-based eGFR minus creatinine-based eGFR) and incident atrial fibrillation (AF) among>340,000 participants from the UK Biobank Study. Compared with those with a near zero eGFR difference, participants with a negative eGFR difference had a higher risk of AF, while those with a positive eGFR difference had a lower risk. These findings suggest that measuring eGFR differences may help identify individuals at a higher risk of developing AF.

Deficiency of circadian clock gene Bmal1 exacerbates noncanonical inflammasome-mediated pyroptosis and lethality via Rev-erbα-C/EBPß-SAA1 axis.

Circadian arrhythmia has been linked to increased susceptibility to multiple inflammatory diseases, such as sepsis. However, it remains unclear how disruption of the circadian clock modulates molecular aspects of innate immune responses, including inflammasome signaling. Here, we examined the potential role of the circadian clock in inflammasome-mediated responses through myeloid-specific deletion of BMAL1, a master circadian clock regulator. Intriguingly, Bmal1 deficiency significantly enhanced pyroptosis of macrophages and lethality of mice under noncanonical inflammasome-activating conditions but did not alter canonical inflammasome responses. Transcriptome analysis of enriched peritoneal myeloid cells revealed that Bmal1 deficiency led to a marked reduction in Rev-erbα expression at steady state and a significant increase in serum amyloid A1 (SAA1) expression upon poly(I:C) stimulation. Notably, we found that the circadian regulator Rev-erbα is critical for poly(I:C)- or interferon (IFN)-ß-induced SAA1 production, resulting in the circadian oscillation pattern of SAA1 expression in myeloid cells. Furthermore, exogenously applied SAA1 markedly increased noncanonical inflammasome-mediated pyroptosis of macrophages and lethality of mice. Intriguingly, our results revealed that type 1 IFN receptor signaling is needed for poly(I:C)- or IFN-ß-induced SAA1 production. Downstream of the type 1 IFN receptor, Rev-erbα inhibited the IFN-ß-induced association of C/EBPß with the promoter region of Saa1, leading to the reduced transcription of Saa1 in macrophages. Bmal1-deficient macrophages exhibited enhanced binding of C/EBPß to Saa1. Consistently, the blockade of Rev-erbα by SR8278 significantly increased poly(I:C)-stimulated SAA1 transcription and noncanonical inflammasome-mediated lethality in mice. Collectively, our data demonstrate a potent suppressive effect of the circadian clock BMAL1 on the noncanonical inflammasome response via the Rev-erbα-C/EBPß-SAA1 axis.